Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma
Mutations in the catalytic domain of the histone methyltransferase EZH2 have been identified in subsets of non-Hodgkin lymphoma (NHL) patients, suggesting an oncogenic dependence on EZH2 enzymatic activity. We previously reported the discovery of EPZ005678 and EPZ-6438, potent and selective S-adenosyl-methionine-competitive inhibitors of EZH2. While both compounds share similar mechanisms and selectivity, EPZ-6438 exhibits enhanced potency and favorable drug-like properties, including good oral bioavailability in animals.
In this study, we characterize EPZ-6438 in preclinical NHL models. EPZ-6438 selectively inhibits H3K27 methylation in a concentration- and time-dependent manner in both wild-type and mutant EZH2 lymphoma cells. Inhibition of H3K27 trimethylation (H3K27Me3) selectively induces cell death in EZH2-mutant human lymphoma cell lines. In EZH2-mutant NHL xenograft models, EPZ-6438 treatment leads to dose-dependent tumor growth inhibition, including complete and sustained regressions, accompanied by reduced H3K27Me3 levels in tumors and selected normal tissues. Notably, mice treated orally with EPZ-6438 for 28 days remained tumor-free for up to 63 days after treatment cessation.
These findings underscore the oncogenic dependency of EZH2-mutant NHL on EZH2 activity and support the potential of EPZ-6438 as a targeted therapeutic in genetically defined lymphomas.